Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction
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ABSTRACT:
PROVIDER: PRJNA1057043 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27345176.fastq.gz | Fastqsanger.gz | |||
| SRR27345177.fastq.gz | Fastqsanger.gz | |||
| SRR27345178.fastq.gz | Fastqsanger.gz | |||
| SRR27345179.fastq.gz | Fastqsanger.gz | |||
| SRR27345180.fastq.gz | Fastqsanger.gz |
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Project description:Microvascular dysfunction has been proposed to drive heart failure with preserved ejection fraction (HFpEF), but the initiating molecular and cellular events are largely unknown. Our objective was to determine when microvascular alterations in HFpEF begin, how they contribute to disease progression, and how pericyte dysfunction plays a role herein. We aimed to assess microvascular dysfunction with respect to the development of cardiac dysfunction, in the Zucker fatty and spontaneously hypertensive (ZSF1) obese rat model of HFpEF at three time points: 6, 14, and 21 weeks of age. We found that pericyte loss was the earliest and strongest microvascular change, occurring before prominent echocardiographic signs of diastolic dysfunction were present. Pericytes were shown to be less proliferative and had a disrupted morphology at 14 weeks in the obese ZSF1 animals, who also exhibited an increased capillary luminal diameter and disrupted endothelial junctions. Pericytes exposed to oxidative stress in vitro showed downregulation of cell cycle associated pathways, and induced a pro-inflammatory state in endothelial cells upon co-culture. We propose pericytes are important for maintaining endothelial cell function, where loss of pericytes enhances the reactivity of endothelial cells to inflammatory signals and promotes microvascular dysfunction, thereby accelerating the development of HFpEF.
2023-12-29 | GSE251995 | GEO
Project description: Not available
| S-EPMC10763525 | biostudies-literature
Project description:Background: The differentiation of pericytes into myofibroblasts causes microvascular degeneration, extracellular matrix (ECM) accumulation, and tissue stiffening, characteristics of fibrotic diseases. It is unclear how pericyte-myofibroblast differentiation is regulated in the microvascular environment. Our previous study established a novel two-dimensional platform for coculturing microvascular endothelial cells (ECs) and pericytes derived from the same tissue. This study investigated how ECM stiffness regulated microvascular ECs, pericytes, and their interactions. Methods: Primary microvessels were cultured in the TGM2D medium. Stiff ECM was prepared by incubating ECM solution in regular culture dishes for one hour followed by PBS wash. Soft ECM with Young’s modulus of approximately 6 kPa was used unless otherwise noted. Bone grafts were prepared from the rat skull. Immunostaining, RNA sequencing, qRT-PCR, western blotting, and knockdown experiments were performed on the cells. Results: Primary microvascular pericytes differentiated into myofibroblasts (NG2+αSMA+) on stiff ECM, even with the TGFβ signaling inhibitor A83-01. Soft ECM and A83-01 cooperatively maintained microvascular stability while inhibiting pericyte-myofibroblast differentiation (NG2+αSMA-/low). We thus defined two pericyte subpopulations: primary (NG2+αSMA-/low) and activated (NG2+αSMA+) pericytes. Soft ECM promoted microvascular regeneration and inhibited fibrosis in bone graft transplantation in vivo. As Integrins are the major mechanosensor, we performed qRT-PCR screening of Integrin family members selected from RNA sequencing data. We found that Integrin β1 (Itgb1) was the major subunit downregulated by soft ECM and A83-01 treatment. Knocking down Itgb1 suppressed myofibroblast differentiation on stiff ECM. Interestingly, ITGB1 phosphorylation (Y783) was mainly located on microvascular ECs on stiff ECM, which promoted EC secretion of paracrine factors, including CTGF, to induce pericyte-myofibroblast differentiation. CTGF knockdown or monoclonal antibody treatment partially reduced myofibroblast differentiation, implying the participation of multiple pathways in fibrosis formation. Conclusions: Microvascular ECs mediate ECM stiffness-induced pericyte-myofibroblast differentiation through paracrine signaling.
2023-07-18 | GSE237069 | GEO
Project description:Early diastolic dysfunction precedes the development of HFpEF, but the molecular events that initiate this process remain poorly defined. HFpEF arises in the setting of systemic comorbidities such as obesity, hypertension, hyperglycemia, and sleep apnea, which often coexist and make it difficult to distinguish their individual contributions to early cardiac remodelling. Here, we aimed to define the early, comorbidity-specific mechanisms that initiate diastolic dysfunction across major HFpEF-associated conditions.
2026-07-03 | E-MTAB-16848 | biostudies-arrayexpress
Project description:Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF
| PRJNA1301320 | ENA
Project description:The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB. The brain microvascular fragments were isolated from mice with different genotypes, each represented by 3-4 biological replicates. Genotypes 1-2: Platelet derived growth factor-B (PDGF-B) retention-motif knockout (pdgfbret/ret) represent the pericyte-deficient situation, and the heterozygous mice (pdgfbret/+) are used as controls. Genotypes 3-4: Hypomorphic PDGF-B mutants that rescue pdgfb-/- null mice, in which a one copy of a conditionally silent human PDGF-B transgene targeted to the Rosa 26 locus (R26P) is turned on by endothelial-specific expression of Cre recombinase. In this data set these mice are named as Tie2Cre, R26P+/0, pdgfb-/- (representing the pericyte-deficient situation). Mice wt for pdgfb (pdgfb+/+) and carrying one silent copy of R26P (R26P+/0), are used as controls. Genotype 5: Adult Notch3+/+ wildtype (WT).
2010-10-21 | E-GEOD-15892 | biostudies-arrayexpress
Project description:The microvasculature plays a key role in tissue perfusion, transport of mediators, and exchange of gases and metabolites to and from tissues. Microvascular dysfunction has emerged as an important contributor to cardiovascular diseases. In this study we used human blood vessel organoids (BVOs) as a model of the microvasculature to delineate the mechanisms of microvascular dysfunction caused by metabolic rewiring. BVOs fully recapitulated key features of the normal human microvasculature, including reliance of mature endothelial cells (ECs) on glycolytic metabolism, as concluded from metabolic flux assays using 13C-glucose labelling and mass spectrometry-based metabolomics. Pharmacological targeting of PFKFB3, a potent activator of glycolysis, with two different chemical inhibitors resulted in rapid BVO restructuring, vessel regression with reduced pericyte coverage. PFKFB3 mutant BVOs also displayed similar structural remodelling compared to control BVOs. Proteomic analysis of the BVO secretome revealed remodelling of the extracellular matrix and differential expression of paracrine mediators such as CTGF. Treatment with recombinant CTGF recovered tight junction formation and increased pericyte coverage in microvessels. Our metabolic and proteomics findings demonstrate that BVOs rapidly undergo restructuring in response to metabolic changes and identify CTGF as a critical paracrine regulator of microvascular integrity.
2023-09-13 | PXD041780 | Pride
Project description:Sorbin and SH3 domain–containing protein 2 (Sorbs2) is a cytoskeletal adaptor protein implicated in cardiomyocyte adhesion, cytoskeletal remodeling, and calcium handling. We investigated its role in diastolic dysfunction using Sorbs2 knockout (KO) mice. Sorbs2 KO mice developed progressive diastolic dysfunction with preserved systolic function, accompanied by left atrial enlargement, pulmonary edema, myocardial fibrosis, increased microtubule detyrosination, and impaired calcium handling. Bulk RNA-seq was performed on ventricular myocardium from wild-type (WT) and KO mice at 6 weeks and 6 months of age, with additional rescue experiments using AAV9-mediated re-expression of Sorbs2. RNA-seq revealed activation of extracellular matrix pathways and integrin signaling in KO mice, while mitochondrial metabolic pathways were downregulated. These data establish Sorbs2 as a critical regulator of diastolic function.
2026-05-21 | GSE306787 | GEO
Project description:Background While the role of pericytes in blood-brain barrier (BBB) disruption and neuroinflammation is well-established in adult neurological disorders, their contribution to neonatal brain injury is largely unexplored. Here, we investigated the role of brain pericytes in hypoxic-ischemic (HI) brain injury in the developing brain, with a particular focus on the regulatory role of pericyte-derived microRNA210 (miR210) in pericyte dysfunction. Methods HI brain injury was induced on postnatal day 9 transgenic mice, including Atp13a5-tdTomato brain pericyte reporter mice, pericyte-specific diphtheria toxin receptor mice, miR210 knockout mice, and wild-type controls. Post-injury assessments include brain infarct, brain edema, BBB permeability, ELISA, western blotting, immunostaining, and neurological function test. BBB-associated cells, including pericytes and endothelial cells, were isolated from mouse brain using an immunomagnetic approach. RNA sequencing analysis was conducted to examine transcriptomic changes in pericytes after HI. To investigate the regulatory role of miR210 in pericyte dysfunction and its underlying mechanisms, primary pericytes were transfected with miR210 mimic or negative control, followed by oxygen-glucose deprivation. Transfected cells were also treated with either interleukin 1 type 1 receptor neutralizing antibody or recombinant interleukin 1 type 2 receptor chimera protein. Post-assays included RT-qPCR, immunostaining and cell viability assay. Student’s t test or one-way ANOVA followed by Bonferroni test was used, as appropriate. Results HI resulted in a time-dependent loss of pericytes in pericyte reporter mouse pups. Ablation of brain pericytes exacerbated BBB disruption and HI brain injury in neonatal brain. miR210 deletion mitigated brain pericyte loss and BBB leakage post-HI. Transcriptomic analysis revealed that HI-induced pericyte dysfunction was associated with upregulated genes enriched in biological processes such as “cellular response to interleukin 1”. miR210 knockout suppressed the expression of proinflammatory markers such as Il1r1. Mechanistically, miR210 overexpression increased proinflammatory cytokine levels and promoted pericyte cell death under oxygen-glucose deprivation, effects that were reversed by IL1R1 blockade. Importantly, brain pericyte-specific miR210 deletion preserved pericyte viability and BBB integrity, and provided neuroprotection after HI. Conclusions These findings underscore the critical role of brain pericytes in BBB function in the developing brain and identify miR210 as a central regulator of pericyte dysfunction following neonatal HI brain injury.
2026-01-14 | GSE312452 | GEO
Project description:Sex Differences in Heart Mitochondria: Relationship to Diastolic Dysfunction
| PRJNA799318 | ENA